Diverse p63 and p73 isoforms regulate Delta 133p53 expression through modulation of the internal TP53 promoter activity

In response to stress, p53 binds and transactivates the internal TP53 promoter, thus regulating the expression of its own isoform, ?133p53a. Here, we report that, in addition to p53, at least four p63/p73 isoforms regulate ?133p53 expression at transcriptional level: p63ß, ?Np63a, ?Np63ß and ?Np73?. This regulation occurs through direct DNA-binding to the internal TP53 promoter as demonstrated by chromatin immunoprecipitation and the use of DNA-binding mutant p63. The promoter regions involved in the p63/p73-mediated transactivation were identified using deleted, mutant and polymorphic luciferase reporter constructs. In addition, we observed that transient expression of p53 family members modulates endogenous ?133p53a expression at both mRNA and protein levels. We also report concomitant variation of p63 and ?133p53 expression during keratinocyte differentiation of HaCat cells and induced pluripotent stem cells derived from mutated p63 ectodermal dysplasia patients. Finally, proliferation assays indicated that ?133p53a isoform regulates the anti-proliferative activities of p63ß, ?Np63a, ?Np63ß and ?Np73?. Overall, this study shows a strong interplay between p53, p63 and p73 isoforms to orchestrate cell fate outcome.